The goal of this proposal is to reduce the morbidity and mortality from prostate cancer. Three major projects form the basis for this work: Project 1 Gene-environment Study of Familial Prostate Cancer; Project 2 Surrogate Endpoint Biomarkers (SEBs) in Prostate Cancer Chemoprevention; and Project 3 Randomized, Placebo-Controlled, Double-Blind Phase IIb Chemoprevention Trial of Difluoromethylornithine in Brothers and First-Cousin Males of Familial Prostate Cancer Probands. These projects will be supported by Administrative and Biostatistical Cores. The strategy is to identify early age onset familial prostate cancer and to define underlying genetic abnormalities and environmental risk factors. Brothers and first-cousin males of early age onset familial prostate cancer probands will be recruited into a phase IIB chemoprevention trial. Baseline characterization of the recruited participants will include free and total PSA density and polyamine content, histopathology (including PIN status), and progression related SEBs in the prostate gland. Participants will be equally randomized to DFMO (moderate-dose), DFMO (low-dose), or placebo, monitored carefully, and restudied after one year. These studies should provide us unique insights into the biology of human prostate carcinogenesis and its potential chemoprevention.